Medulloblastoma is the most common primary central nervous system tumor which arises in childhood. Its management represents both the progress and limitations involved in patient care over the last 20 years.

Medulloblastomas arise in the fourth ventricle, between the brain stem and the cerebellum. Common symptoms are unsteadiness, headaches, and vomiting due to hydrocephalus (from blockage of cerebrospinal fluid flow). Diagnosis is usually within one to three months of the onset of symptoms, as this is a fast-growing tumor. Occasionally due to bleeding within the tumor, a patient will be in a coma or severe distress at diagnosis. While there has been significant improvement in survival for children with this disease, much progress needs to be made.

Histologically similar tumors may also be seen in the pineal region or the cerebral cortex (the thinking part of the brain). It is uncertain whether tumors which arise in these different areas of the brain are identical to medulloblastoma in their biologic behavior, as the actual cell of origin of the medulloblastoma remains unknown. Despite many investigations, the "medulloblast" has never been identified. Factors which account for the development of the medulloblastoma, its tendency to spread outside of its primary site of origin, or its ability to withstand chemotherapy and radiation are unknown.

Treatment has evolved over the past 30 years with the majority of patients requiring surgery, radiation, and chemotherapy. Over the past 20 years, surgery for children with medulloblastoma has become safer, yet two of every ten children will develop severe, sometimes irreversible, neurologic problems afterwards, including loss of speech and severe balance difficulties. These problems may not be apparent for 24 hours after surgery and such complications have been called the "pseudobulbar syndrome" or "postcerebellar surgery mutism syndrome." There is strong evidence that medulloblastomas which are only biopsied at the time of surgery are very difficult to control, despite the use of radiation and chemotherapy. Children whose tumors are resected (totally when possible) have a better overall rate of survival.

Medulloblastoma has the tendency to spread to other sites in the nervous system and, infrequently, to other body organs. Staging studies are needed and they include cerebrospinal fluid analysis (spinal taps) for evaluation of tumor cells within the spinal fluid, and MRI scans (head and spine), performed with and without contrast agents. Newer molecular genetic tests are under study and may add to the ability to predict the behavior of medulloblastomas. Factors, such as the expression of TrkC, erb-B, and n-myc, may be extremely important; but these tests are not yet commercially available and must still be considered research tools.

Radiation to the entire brain and spine at the time of diagnosis, with additional radiation (boost) to the tumor site, has been a major treatment advance. With it, the overall five-year survival rate has risen from 20% to well over 50% in the last 20 years.

Over the past ten years, there has been increasing evidence that chemotherapy improves survival for children whose tumors cannot be fully resected, or have spread beyond the primary site (disseminated) at diagnosis. In a study originating at Children's Hospital of Philadelphia and completed at Children's National Medical Center in Washington, D.C., eight out of ten children with high-risk medulloblastoma were alive and disease-free five years from diagnosis, many likely cured of their disease. Studies are underway to determine what type of chemotherapy is most effective and safest for children with medulloblastoma. Some patients may need more aggressive chemotherapy which would delay radiation for a few weeks or months.

Aggressive treatment approaches, especially craniospinal irradiation, can harm the developing brain. It is hard to predict what dose of radiotherapy will be harmful in each individual child. It is well known that very young children will have significant learning problems from full-dose radiotherapy and older children may have difficulties in school. A decrease in dosage may also decrease its efficacy on the tumor. Approaches using reduced-dose craniospinal irradiation and chemotherapy, to decrease cognitive, endocrinologic, and psychological deficits, are being evaluated. They may decrease late effects, but carry with them the risk of having more disease failures.

Studies attempting to delay and possibly even obviate radiotherapy in children less than three years of age, are also underway using high-dose, multiple agent chemotherapy, given immediately after surgery, in an attempt to stop the tumor from growing. Other studies are also employing chemotherapy put directly into the cerebrospinal fluid. Autologous bone marrow transplant or peripheral stem cell rescue, with growth factors that stimulate white blood cell production, are being utilized now and must be closely evaluated for overall safety.

In summary, significant progress has been made in the management of childhood medulloblastoma. Prognosis has changed from two to eight out of every ten children being disease-free and potentially cured five years from diagnosis, due to aggressive surgery, radiation therapy, and chemotherapy. For some children, especially those that are very young or have disseminated disease at diagnosis, survival is not as good. A great deal of work needs to be done in determining the biology of this common childhood brain tumor, what its cell origin is, and what controls growth. Only through the understanding of the biology of this tumor can the goal of curing children with medulloblastoma be achieved. In addition, a great deal of effort is underway in determining ways to make treatment safer for children with this disease, so that they not only survive, but experience a quality of life that will allow them to succeed in school, and in their future lives.

A variety of studies are also open at institutions for children with recurrent medulloblastomas. These include the use of new chemotherapeutic agents: Irinotecan (Children's National Medical Center); Temozolomide and 0-6-benzyl-guanine (Children's National Medical Center/NIH - soon to be Pediatric Brain Tumor Consortium (PBTC); and a variety of newer biologic agents.

A second pilot study (already open) will utilize an even further-reduced dose of craniospinal radiation therapy for children with medulloblastoma (reducing radiation from 2400 cGy of cranial radiation to 1800 cGy).

As has already been noted, there are multiple studies looking at ways to potentially improve outcome for children with high-risk or poor-risk disease. High-dose chemotherapy with peripheral stem cell rescue is no longer being given prior to radiation, but is now being given following radiation to try to improve survival. A second approach has attempted to use intrathecal chemotherapy to control leptomeningeal disease or to prevent leptomeningeal disease relapse. This approach is already underway in infants and may soon be utilized for older patients with disseminated and potentially, in the future, non-disseminated disease at the time of diagnosis.

Studies Open or Soon To Be Opened for Children with Medulloblastoma
in the Washington, DC Region.

Study

Treatment of Children with Average-Risk Medulloblastoma with Reduced-Dose Radiation Therapy and One of Two Chemotherapies: A Phase III CCG/POG Study

Children (greater than 3 years of age) with non-disseminated medulloblastomas

Comments

This is a randomized study comparing two different chemotherapeutic approaches but utilizing a reduced-dose craniospinal radiation therapy for all patients; the study has accrued nearly 400 patients. The study closed December 2000.

Study

Treatment of Children with Average-Risk Medulloblastoma with Reduced-Dose Radiotherapy and VCR, CCNU and CPPD Chemotherapy

Participating Institutions

Children's National Medical Center

Eligibility

Children (greater than 3 years of age) with disseminated or otherwise poor-risk medulloblastoma

Comments

This is a continuation of a study demonstrating a greater than 80% five-year survival rate in children with medulloblastoma

This currently open study utilizes high-dose chemotherapy and peripheral stem cell rescue for infants with malignant brain tumors in an attempt to improve survival and delay, if not obviate, the need for radiotherapy

Study

Treatment of Children with Poor-risk Medulloblastoma (Children's Cancer Group 99701)

Participating Institutions

Children's National Medical Center, Georgetown University

Eligibility

Children (less than 3 years of age) with disseminated poor-risk medulloblastoma or primitive neuroectodermal tumors outside the posterior fossa

Comments

This is a trial utilizing a drug (carboplatinum) in combination with radiation for children with poor-risk medulloblastoma. This is a Phase I/II trial.

Study

Treatment of Children with Poor-risk Medulloblastoma (Children's Cancer Group 99703)

Participating Institutions

Children's National Medical Center

Eligibility

Children (greater than 3 years of age) with disseminated or poor-risk medulloblastoma

Comments

This is a study utilizing radiation followed by 3 cycles of high-dose chemotherapy with peripheral stem cell rescue for children with poor-risk medulloblastoma.

Study

High-dose Chemotherapy plus Intrathecal Chemotherapy and Deferred Local Radiotherapy for Children Less than 3 Years with Medulloblastoma (Pediatric Brain Tumor Consortium Study 001)

Participating Institutions

Children's National Medical Center (with Consortium), including Inova Fairfax Hospital and Georgetown University

Eligibility

Children (less than 3 years) with malignant brain tumors, including medulloblastoma

Comments

This is an innovative study utilizing intrathecal chemotherapy with high-dose chemotherapy in an attempt to defer radiotherapy for children with medulloblastoma. Focal radiation therapy is recommended following completion of treatment.

Children (less than 3 years) with malignant brain tumors, including medulloblastoma

Comments

This is a study utilizing high-dose chemotherapy for 3 cycles, followed by 3 cycles of higher-dose chemotherapy with peripheral stem cell rescue for children less than 3 years with malignant brain tumors.

Study

Reduced-dose Radiotherapy and Post Radiotherapy Chemotherapy for Children between 3 and 7 years of age with Meduloblastoma

Participating Institutions

Children's National Medical Center

Eligibility

Children (between 3 and 7 years) with medulloblastoma

Comments

This is a pilot study using 1800 cGy of CSRT and a more aggressive post-radiotherapy chemotherapy regimen.